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研究生：	黃文忠 Wen-Chung Huang
論文名稱：	絞股藍抑制OVA致敏小鼠呼吸道發炎反應 Gynostemma pentaphyllum attenuates airways inflammation in OVA-sensitized asthmatic mice
指導教授：	李銘亮 Li, Ming-Liang 郭敏玲 Kuo, Ming-Ling
學位類別：	博士 Doctor
系所名稱：	生命科學系 Department of Life Science
論文出版年：	2008
畢業學年度：	96
語文別：	英文
論文頁數：	130
中文關鍵詞：	絞股藍、氣喘、輔助型T 細胞、呼吸道過度反應、細胞激素
英文關鍵詞：	Gynostemma pentaphyllum, asthma, T helper cells, airway hyperresponsiveness, cytokines
論文種類：	學術論文
相關次數：	點閱：220 下載：6
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氣喘是一種慢性氣管發炎反應的疾病，在發作時常有窒息致命的危險性。氣喘患者發病時的病徵會出現呼吸困難、喘嗚音、胸悶和咳嗽等症狀，甚至會出現呼吸道收縮狹窄，呼吸道黏液增加，導致呼吸道被黏液阻塞窒息死亡。慢性氣喘患者呼吸道會出現大量嗜酸性球浸潤的現象，以及呼吸道過度反應 (airways hyperresponsiveness，AHR)的情形；更多的研究發現，Th2細胞所分泌的IL-4、IL-5、IL-9以及IL-13等細胞激素主要影響氣喘的病理表現，如果可以抑制Th2的細胞活化以及相關的激素分泌，將有助於減低氣喘的症狀。雖然類固醇是一種普遍用來治療氣喘的藥物，但其除了具有抑制免疫功能與呼吸道發炎的療效之外，也會出現許多不當的副作用，所以東方與西方醫學界都希望可以尋找更多的方法來治療氣喘的疾病。絞股藍 (Gynostemma pentaphyllum，又名七葉膽)為葫蘆科絞股藍屬的植物，因為生長分佈區域，加上已經被鑑定出之90多種絞股藍皂甙 (gypenoside)中，有六種與人蔘的皂甙相同，故絞股藍又有南方人蔘之稱。並且近年來學者對於絞股藍的藥理與臨床研究發現，絞股藍在臨床上有極多的功效；包括降血脂、血糖、抗衰老、抗腫瘤、增強免疫力等的作用。
我們發現接受腹腔注射或口服絞股藍抽出物5天的小鼠，其脾臟細胞分泌較高的Th1相關的細胞激素與IgG2a，並且可抑制Th2 相關細胞激素的分泌。所以絞股藍可能具有調節與改變Th1及Th2細胞之間的細胞激素分泌平衡性的能力，或許可以抑制氣喘病人體內較強的Th2活性，應該具有減緩氣喘病情的療效。本論文以雞卵蛋白 (ovalbumin, OVA) 為過敏原，引起小鼠產生呼吸道發炎等氣喘病徵，來測試絞股藍是否具有減緩氣喘的發炎與抑制其Th2活性的反應。我們設計幾個實驗模式，在先以腹腔注射致敏並吸入OVA 3次的IH3 模式中，OVA致敏小鼠餵食7天絞股藍抽出物，發現這些小鼠呼吸道過度反應、嗜酸性球浸潤與血清的OVA-IgE有明顯下降的現象；若再吸入過敏原 2次，除了更明顯抑制發炎病徵之外，也可以顯著抑制OVA-刺激培養之脾臟細胞分泌 Th2細胞激素。此外，我們亦以3個長期給藥模式，來檢定絞股藍抽出物是否對氣喘小鼠具有預防 (T-A 模式)、長期預防加治療 (T-B 模式)、或是長期治療 (T-C 模式) 的效果。實驗結果顯示，於T-A 實驗模式中，絞股藍抽出物並無法顯著降低AHR、嗜酸性球浸潤、以及血清的OVA-IgE等的發炎病徵。但是在T-A模式口服絞股藍的小鼠，在接觸過敏原的階段持續口服絞股藍 (T-B 模式)，以及一開始接觸過敏原之後就長期給予絞股藍抽出物 (T-C 模式)，兩者都可以有效減緩氣喘小鼠的發炎病徵與抑制其Th2活性的反應。綜合所有OVA致敏小鼠的實驗模式試驗，我們認為絞股藍具有治療氣喘模式小鼠的呼吸道發炎反應與抑制過度免疫反應的效果，但卻無法有效預防氣喘的發生。

Asthma is characterized as a chronic disease which causes an important public health problem worldwide. The symptoms of asthma include wheezing, cough, shortness of breath, airway narrowing and mucus increase cause suffocation and death. In addition, more eosinophils infiltration and airways hyperresponsiveness (AHR) are usually found in the airways of asthmatic patients. The Th2-type cytokines appear to be crucial in the pathogenesis of asthma. Thus, to suppress Th2-induced cytokines secretion might be able to inhibit asthma symptoms. Steroid is commonly used to treat asthma. Although it suppresses the respiratory track inflammation, long-term usage of steroids may cause potential side effects. Therefore, doctors in Western and Chinese medicine desire to have alternative ways to treat asthma. Gynostemma pentaphyllum is a perennial liana plant and widely used as an herbal tea in Japan, southern China and Taiwan. About 90 different gypenosides have been identified from the extract of G. pentaphyllum. Among them, six gypenosides are the same with the ginsenosides from Panax ginseng. Recent studies found that G. pentaphyllum has additional pharmacological effects on the inhibition of blood-sugar, hyperlipidaemia, and the treatment of hepatitis.
Our results indicated that the extract of G. pentaphyllum could promote the expression of Th1 cytokines and IgG2a secretion from splenocytes of mice that were intraperitoneally injected or orally administrated with the extract for 5 consecutive days. Since more Th2-associated cytokines in lung were found in asthmatic patients, we proposed that G. pentaphyllum might be able to module the balance of Th1/Th2 cytokines and to suppress the inflammation in asthma airways. Chicken ovalbumin (OVA) was used as the allergen to induce asthmatic immune responses and symptoms. We tested the efficacy of G. pentaphyllum in 5 experimental models. BALB/c mice were firstly sensitized with intraperitoneal injection and challenged with 3 times of OVA inhalation (IH3 model) or 5 times (IH3 model). G. pentaphyllum was orally administrated for 7 consecutive days before the end of the OVA challenge. Asthmatic symptoms were examined, including AHR, eosinohpilia in lungs, and serum levels of OVA-specific IgG1 and IgE. The cytokine concentrations of the supernatants of OVA-activated splenocytes were also determined. Oral administration of G. pentaphyllum extracts significantly attenuated AHR and inhibited eosinophil infiltration in mice of both IH3 and IH5 models. Significantly decreased serum OVA-specific antibodies and Th2-type cytokines, as well as the increased IFN- production, were detected in the IH5 model. Moreover, whether the long-administration of G. pentaphyllum was able to prevent asthma was examined in T-A model. The mice received the extract for 28 days before the sensitization with OVA. No significant reduction of asthma symptoms was detected. In the other 2 models, mice received the G. pentaphyllum extract before and during the contact with OVA (the T-B model) and 28 days since the first dose of OVA injection (the T-C model). The result showed that G. pentaphyllum extract could significantly attenuate inflammatory responses and Th2-cell activity. Therefore, the results suggested that G. pentaphyllum inhibited airway inflammation and over-active immune responses, but can not prevent the symptoms in asthmatic mice.

Chapter 1: Literature Review                             1
    1-1 Background and epidemiology of asthma                        1
    1-2 Pathogenesis of asthma                                       3
    1-3 The role of Th cells in pathogenesis of asthma                     5
    1-4 Therapy of asthma                                            8
1-5 Introduction of Gynostemma pentaphyllum                       9
1-5-1 Effect on hyperlipidaemia                                  10
1-5-2 Effect on blood embolism                                  11
1-5-3 Effects on cardiovascular system                             11
1-5-4 Effect on hyperglycemia                                   11
1-5-5 Effect on cancer                                          12
    1-6 Background of Chinese herbal medicines to asthma                12
    1-7 Purpose of treat asthma by G. pentaphyllum                      15


Chapter 2 :Material and Methods                          17
    2-1 The experimental animal and commonly used experiment method    17
    2-1-1 Experimental animal                                       17
    2-1-2 Preparation of G. pentaphyllum extracts                        17
    2-1-3 Serum collection                                          18
    2-1-4 Splenocyte isolation                                       18
    2-1-5 ELISA assay for total immunoglobulins                        19
    2-1-5-1 IgG                                                   19
    2-1-5-2 IgG1 and IgG2a                                         20
    2-1-5-3 IgM                                                   20
    2-1-5-4 IgA                                                   20
    2-1-6 ELISA assay for cytokine concentration                        21
    2-1-7 Measurement of airway hyperresponsiveness (AHR)             22
    2-1-8 Bronchoalveolar lavage fluid (BALF) collection                 22
    2-1-9 Lung histology                                            22
    2-1-10 Statistics analysis                                         23
    2-2 Immune regulatory function of G. pentaphyllum                    23
    2-2-1 BALB/c mice were received intraperitoneal injection of
G. pentaphyllum                                           23
    2-2-2 Short-term oral administration of G. pentaphyllum extracts         24
    2-2-3 Spleen cell cultures                                        24
    2-2-4 Analysis of serum ALT and AST                              25
    2-2-5 Histological examination                                    25
    2-3 The effect of G. pentaphyllum on airway inflammation of
OVA-sensitized mice                                         26
    2-3-1 Experimental evaluation of whether G. pentaphyllum inhibited
airway inflammatory in the asthmatic mice of IH3 model           26
    2-3-1-1 Mice sensitization and drug treatment                        26
    2-3-2 Experimental evaluation of treating asthma with G. pentaphyllum inhibited airway inflammatory in the mice of IH5 model           27
    2-3-2-1 Mice sensitization and drug treatment                        27
    2-3-3 Evaluation of preventive effect of G. pentaphyllum extracts in
OVA-sensitized mice                                       28
    2-3-4 Experimental evaluation of preventive and therapeutic asthma
of G. pentaphyllum extracts in OVA-sensitized mice.              29
    2-3-5 Experimental evaluation of therapeutic asthmatic effect of
G. pentaphyllum extracts in OVA-sensitized mice.                30

Chapter 3: Results                                       31
    3-1 Immune regulatory test of G. pentaphyllum                       31
    3-1-1 G. pentaphyllum of intraperitoneally injected in BALB/c mice      31
    3-1-1-1 G. pentaphyllum induced higher levels of immunoglobulin in
mice serum                                            31
    3-1-1-2 G. pentaphyllum enhanced immunoglobulin production from
 spleen cells                                            32
    3-1-1-3 G. pentaphyllum enhanced production of cytokines from
activated spleen cells                                    33
3-1-2 Short-term oral administration of G. pentaphyllum extracts
 modulated immune responses                               34
3-1-2-1 Higher levels of immunoglobulin in mice serum induced
by oral treatment of G. pentaphyllum                        34
    3-1-2-2 G. pentaphyllum enhanced immunoglobulin production from LPS-activated spleen cells                               35
3-1-2-3 G. pentaphyllum changed the production of cytokines from ConA-activated spleen cells                              36
    3-1-2-4 Effect of G. pentaphyllum extract on blood biochemistry
and histopathology of internal organs                      37
3-2 The effect of G. pentaphyllum on airway inflammation of
OVA-sensitized and challenged mice                          38
    3-2-1 To evaluate oral administration of G. pentaphyllum extracts
treated OVA-sensitive mice in IH3 model                     38
    3-2-1-1 G. pentaphyllum attenuated OVA-induced airway
Inflammation                                         38
    3-2-1-2 G. pentaphyllum inhibited serum OVA-specific antibodies      39
    3-2-1-3 G. pentaphyllum reduced IL-5 production by spleen cells from OVA-sensitized mice                                   39
    3-2-2 To evaluate oral administration of G. pentaphyllum extracts
treated OVA-sensitive mice in IH5 model                     40
    3-2-2-1 G. pentaphyllum reduced further allergen-induced airway
inflammation                                         40
    3-2-2-2 G. pentaphyllum inhibited serum OVA-specific antibodies in
the mice of IH5 model                                  41
    3-2-2-3 G. pentaphyllum modulated cytokine secretion by spleen
cells and Th2-type cytokines in BALF from OVA-sensitized
mice                                                42
    3-2-2-4 Histopathologic examination                             43
3-2-3 No significant preventive effect of G. pentaphyllum extracts
was detected in OVA-sensitized mice                        43
    3-2-4 Long-term administration of G. pentaphyllum extracts in OVA-
sensitized mice                                         44
    3-2-4-1 Long-term administration of G. pentaphyllum reduced
allergen-induced airway inflammation                     44
    3-2-4-2 Long-term administration of G. pentaphyllum inhibited serum OVA-specific antibodies                                45
    3-2-4-3 Long-term administration of G. pentaphyllum modulated
cytokine secretion by spleen cells from OVA-sensitized mice    45
3-2-5 The therapeutic effect of long-term administration of G.
pentaphyllum extracts in OVA-sensitized mice               46
    3-2-5-1 Lower dose of oral administration, but not inhalation, of
G. pentaphyllum reduced OVA-induced airway inflammation   46
    3-2-5-2 Lower dose of oral administration of G. pentaphyllum reduced
serum OVA-specific antibodies in asthmatic mice            47
    3-2-5-3 Lower dose of oral administration of G. pentaphyllum
modulated cytokine secretion from spleen cells from
OVA-sensitized mice                                   47

Chapter 4: Discussions                                  49
    4-1 G. pentaphyllum effect on immune modulation                  49
    4-2 G. pentaphyllum effect on therapy of asthma                   53

Chapter 5: Conclusions                                  62
Chapter 6: References                                   63
Chapter 7: Figures and Tables                            79
                                

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